This invention relates to azolidine derivatives which are xcex23 adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment of type II diabetes.
The subdivision of xcex2 adrenergic receptors (xcex2-AR) into xcex21- and xcex22-AR has led to the development of xcex21- and xcex22-antagonists and/or agonists which have been useful for the treatment of cardiovascular disease and asthma. The recent discovery of xe2x80x9catypicalxe2x80x9d receptors, later called xcex23-AR, has led to the development of xcex23-AR agonists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on xcex23-AR agnoists , see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997, 37, 421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33,193; 3. C. P. Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25, 11.
Compounds that are potent and selective xcex23 agonists, may be potentially useful antiobesity agents. Low levels or lack of xcex21 and xcex22-agonistic properties will minimize or eliminate the adverse side effects that are associated with xcex21 and xcex22 agonistic activities, i.e. increased heart rate, and muscle tremor, respectively.
Early developments in the xcex23-agonist field are described in European patent 427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, 5,153,210. Although the early developments purport to claim compounds with greater xcex23-AR selectivity over the xcex21- and xcex22-AR. However, clinical trials in humans with those early developed xcex23-agonists have, so far, not been successful.
More recently, potent and selective human xcex23 agonists have been described in several patents and published applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO 95/29159, European Patents 659737, 801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in Chinese hamster ovary (CHO) cells test procedures, expressing cloned human xcex23 receptors, which predict the effects that can be expected in humans (Granneman et al., Mol Pharmacol., 1992, 42, 964; Emorine et al., Science, 1989, 245, 1118; Liggett Mol. Pharmacol., 1992, 42, 634).
xcex23-Adrenergic agonists also are useful in controlling the frequent urge of urination. It has been known that relaxation of the bladder detrusor is under beta adrenergic control (Li J H, Yasay G D and Kau S T Pharmacology 1992; 44: 13-18). Beta-adrenoceptor subtypes are in the detrusor of guinea-pig urinary bladder. Recently, a number of laboratories have provided experimental evidence of xcex23 adrenergic receptors in a number of animal species including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, et al. Br. J. Pharmacol. 1998; 124: 593-599), and that activation of the xcex23 receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder.
Urge urinary incontinence is characterized by abnormal spontaneous bladder contractions that can be unrelated to bladder urine volume. Urge urinary incontinence is often referred to hyperactive or unstable bladder. Several etiologies exist and fall into two major categories, myogenic and neurogenic. The myogenic bladder is usually associated with detrusor hypertrophy secondary to bladder outlet obstruction, or with chronic urinary tract infection. Neurogenic bladders are associated with an uninhibited micturition reflex. An upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized my abnormal spontaneous contractions that result in an abnormal sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder includes the use of antimuscarinic agents to block the action of the excitatory neurotransmitter acetylcholine. While effective in neurogenic bladders, their utility in myogenic bladders is questionable. In addition, due to severe dry mouth side-effects associated with antimuscarinic therapy, the patient compliance with these agents is only approximately 30%.
In the bladder, xcex23 adrenergic receptor agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled xcex23 receptor. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits bladder smooth muscle contractility.
It is suggested therefore, that activation of the xcex23 adrenergic receptor in the urinary bladder will inhibit abnormal spontaneous bladder contractions and be useful for the treatment of bladder hyperactivity. Note, that unlike the antimuscarinics, xcex23 adrenergic receptor agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite all these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, frequent urination and related diseases. A potent and selective xcex23 adrenergic receptor agonist is therefore highly desirable for the potential treatment of such disease states.
This invention provides compounds of Formula I having the structure 
wherein,
R1, R2, R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6-10 carbon atoms, halogen, trifluoromethyl of atoms, alkoxy of 1-6 carbon atoms, hydroxy, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkyl amino of 1-6 carbon atoms per alkyl group, formamido, ureido, acyl of 2-7 carbon atoms, acylamino of 2-7 carbon atoms, amino, alkylsulfonylamino of 1-6 carbon atoms, or arylsulfonylamino of 6 to 10 carbon atoms; or two of R1, R2, and R3 are taken together to form a phenyl ring or a heterocyclic ring which is fused to the ring which contains the R1, R2, or R3 substituents, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, or S;
R4 is hydrogen or alkyl of 1-6 carbon atoms;
R5 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-14 carbon atoms, halogen substituted arylalkyl of 7-14 carbon atoms, arylalkene of 8-16 carbon atoms, arylalkyne of 8-16 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, aryloxycarbonyl of 7-11 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or arylsulfonyl of 1-6 carbon atoms;
R6 is hydrogen, alkyl of 1-6 carbon atoms, aryl or arylalkyl of 7-14 carbon atoms;
A is phenyl, naphthyl, benzofuryl, or benzothienyl;
X is bond, xe2x80x94OCH2xe2x80x94, or xe2x80x94SCH2xe2x80x94;
Y is alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms;
Z is carbon, sulfur, oxygen, or nitrogen;
W is carbon or nitrogen;
or a pharmaceutically acceptable salt thereof, which are selective agonists at human xcex23 adrenergic receptors and are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety.
Alkyl includes both straight chain as well as branched moieties. Alkenyl and alkynyl include both straight chain as well as branched moities, which contain at least one alkene or alkyne group. By definition alkyl also includes alkyl moieties which are optionally mono- or poly substituted with groups such as halogen, hydroxy, cyano, alkoxy, aryloxy, arylalkyl, alkylthio, arylthio, amino, alkylamino, and dialkylamino. Halogen means bromine, chlorine, fluorine, and iodine. Preferred aryl moieties are phenyl and naphthyl.
As used herein, a heterocyclic ring is a ring containing 1-3 heteroatoms selected from N, O, and S, which may be saturated, unsaturated, or partially unsaturated. It is understood that the heterocyclic ring does not contain heteroatoms in arrangements which would make them inherently unstable. For example, the term heterocyclic ring does not include ring systems containing Oxe2x80x94O bonds in the ring backbone. When any two of R1, R2, or R3 are taken together to form a heterocyclic ring, the resulting heterocycle will be fused to a phenyl ring. Either ring of the phenyl fused heterocycle may contain the R1, R2, or R3 substitutent which is not part of the ring backbone. Similarly when any two R1, R2, or R3 are taken together to form a phenyl ring, the resulting moiety will be a naphthyl ring. Either ring of the naphthyl moiety may contain the R1, R2, or R3 substitutent which is not part of the ring backbone. When two of R1, R2, or R3 are taken together to form a heterocyclic ring, preferred phenyl fused heterocyclic rings include benzimidazolone and carbazole.
The compounds of the present invention contain at least one asymmetric center. Additional asymmetric centers may exist on the molecule depending upon the structure of the substituents on the molecule. The compounds may be prepared as a racemic mixture and can be used as such, or may be resolved into the individual isomers. In addition to covering the racemic compounds, this invention also covers all individual isomers, enantiomers, diasteromers or mixtures thereof, regardless of whether the structural representations of the compounds indicate such stereochemistry.
Preferred compounds of Formula I are those in which
R1, R2, R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6-10 carbon atoms, halogen, arylalkoxy of 7-14 carbon atoms, arylalkyl of 7-14 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or alkylsulfonylamino of 1-6 carbon atoms; or two of R1, R2, and R3 are taken together to form a heterocyclic ring which is fused to the ring which contains the R1, R2, or R3 substituents, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, or S;
R4 is hydrogen or alkyl of 1-6 carbon atoms;
R5 is hydrogen, alkyl of 1-6 carbon atoms, halogen substituted arylalkyl of 7-14 carbon atoms, or arylalkyne of 8-16 carbon atoms;
R6 is hydrogen, or alkyl of 1-6 carbon atoms;
A is phenyl, or benzofuryl;
X is bond, or xe2x80x94OCH2xe2x80x94;
Y is alkyl of 1-6 carbon atoms;
Z is sulfur;
W is carbon or nitrogen;
or a pharmaceutically acceptable salt thereof.
Specifically preferred compounds of this invention are:
a) 5-[4-(2-{[(2S)-2-Hydroxy-3-(4-phenoxyphenoxy)propyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
b) 5-{4-[2-({(2S)-3-[4-(Benzyloxy)phenoxy]-2-hydroxypropyl}amino)ethyl]anilino}-3-methyl-1,3-thiazolidine-2,4-dione;
c) 5-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)anilino]-3-methyl-1,3-thiazolidine-2,4-dione;
d) 5-{4-[2-({(2S)-3-[4-(Benzyloxy)phenoxy]-2-hydroxypropyl}amino)ethyl]anilino}-1,3-thiazolidine-2,4-dione;
e) 5-[4-(2-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
f) 5-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxy-ethyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
g) 5-[4-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
h) 5-[4-(2-{[(2S)-3-(4-Fluorophenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
i) 5-[4-(2-{[(2S)-2-Hydroxy-3-phenoxypropyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
j) 5-[4-(2-{[(2S)-2-Hydroxy-3-(4-methoxyphenoxy)propyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
k) 5-{4-[2-({(2S)-3-[3-(Benzyloxy)phenoxy]-2-hydroxypropyl}amino)ethyl]anilino}-1,3-thiazolidine-2,4-dione;
l) 5-[4-(2-{[(2S)-2-Hydroxy-3-(3-hydroxyphenoxy)propyl]aminolethyl)anilino]-1,3-thiazolidine-2,4-dione;
m) 5-[4-(2-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
n) N-{5-[(1S)-2-({4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)amino]phenethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide;
o) 5-[4-(2-{[(2S)-3-(1-Benzofuran-5-yloxy)-2-hydroxypropyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
p) 5-[4-(2-{[(2S)-3-(4-Butoxyphenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione;
q) 5-[4-(2-{[(2S)-2-Hydroxy-3-phenoxypropyl]amino}ethyl)(methyl)anilino]-1,3-thiazolidine-2,4-dione.;
r) 5-[4-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}propyl)anilino]-1,3-thiazolidine-2,4-dione;
s) 5-{4-[2-({(2R)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)ethyl]anilino}-1,3-thiazolidine-2,4-dione;
t) 5-{[2-({[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}methyl)-1-benzofuran-5-yl]amino}-1,3-thiazolidine-2,4-dione;
u) 5-(4-{2-[(2S)-2-Hydroxy-3-(naphthalen-2-yloxy)-propylamino]-ethyl}-phenylamino)-thiazolidine-2,4-dione;
v) 5-(4-{2-[(2S)-3-(Biphenyl-4-yloxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-thiazolidine-2,4-dione;
w) 5-(4-{2-[2-Hydroxy-3-(naphthalen-1-yloxy)-propylamino]-ethyl}-phenylamino)-thiazolidine-2,4-dione;
x) 5-(4-{2-[(2S)-3-(Benzo[1,3]dioxol-5-yloxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-thiazolidine-2,4-dione;
y) 5-(4-{2-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-thiazolidine-2,4-dione;
z) 5-[(4-{2-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenyl)-(4-bromo-benzyl)-amino]-thiazolidine-2,4-dione;
aa) 5-[(4-{2-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenyl)-methyl-amino]-thiazolidine-2,4-dione;
bb) 5-[(4-{2-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenyl)-[3-(4-fluoro-phenyl)-prop-2-ynyl]-amino}-thiazolidine-2,4-dione;
cc) 5-[(4-Bromo-benzyl)-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenyl)-amino]-thiazolidine-2,4-dione;
dd) 5-((4-Bromo-benzyl)-{4-[2-((2S)-2-hydroxy-3-phenoxy-propylamino)-ethyl]-phenyl}-amino)-thiazolidine-2,4-dione;
ee) 5-{4-[2-((2S)-2-Hydroxy-2-pyridin-3-yl-ethylamino)-ethyl]-phenylamino}-thiazolidine-2,4-dione; and
ff) 5-{4-[2-((2R)-2-Hydroxy-2-pyridin-3-yl-ethylamino)-ethyl]-phenylamino}-thiazolidine-2,4-dione
or a pharmaceutically acceptable salt thereof.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention. 
In Scheme I, hydroxyl compounds of structure 1 which are either commercially available or can be prepared by known methods (ref. EP 0764640), can be alkylated with glycidyl benzenesulfonates 2 in the presence of a base, i.e. sodium hydride to produce epoxides 3. Styrene oxides that were used in this invention were commercially available. Refluxing either epoxides 3 or styrene oxides with aniline 4 produced compounds 5. The amino group can be protected selectively using di-tert-butyl dicarbonate at low temperatures (0xc2x0 C.) to produce carbamates 6. Treatment of the carbamates 6 with bromo-thiazolidinediones 7 in the presence of a base, i.e. triethylamine, in polar solvents, i.e. N,N-dimethylformamide, followed by acidic hydrolysis with either organic or inorganic acids, i.e. trifluoroacetic acid, produced thiazolidinediones 8. The required bromo-thiazolidinediones 7 were prepared according to known methods (ref. J. Med. Chem., 1990, 33 1418-1423). Alkylation of 6 with various alkylating agents 9 in the presence of a base, i.e. potassium carbonate, produced anilines 10. Substituted anilines 10 react with the bromo-thiazolidinediones 7, similarly to anilines 6, to produce alkylated analogues 8. 
In Scheme II, nitrobenzene 11 was treated with acetoxime in the presence of a base, i.e. sodium hydride, followed by treatment with an ethanolic solution of hydrochloric acid to produce benzofuran 13. Bromination of 13 with 1,3-dibromo-5,5-dimethylhydantoin under UV light gave bromide 15. Conversion of 13 to amine 16 was accomplished in two steps, first alkylation with potassium phthalimide in acetonitrile in the presence crown ether (18-C-6), followed by hydrolysis with hydrazine/ethanol. Amine 16 was converted to the thiazolidinedione 17, in substantially the same manner as in Scheme I.
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following standard pharmacological test procedures, which measured the binding selectivity to the xcex21, xcex22, and xcex23 adrenergic receptors. Binding to the receptors was measured in Chinese Hamster ovary (CHO) cells that were transfected with adrenergic receptors. The following briefly summarizes the procedures used and results obtained.
Transfection of CHO cells with xcex21 and xcex22 adrenergic receptors: CHO cells were transfected with human xcex21- or xcex22-adrenergic receptors as described in Tate, K. M., Eur. J. Biochem., 196:357-361 (1991).
Cloning of Human xcex23-AR Genomic DNA: cDNA was constructed by ligating four polymerase chain reaction (PCR) products using the following primers: an ATG-Narl fragment, sense primer 5xe2x80x2-CTTCCCTACCGCCCCACGCGCGATC3xe2x80x2 and anti-sense primer 5xe2x80x2CTGGCGCCCAACGGCCAGTGGCCAGTC3xe2x80x2; a Narl-Accl fragment, 5xe2x80x2TTGGCGCTGATGGCCACTGGCCGTTTG3xe2x80x2 as sense and 5xe2x80x2GCGCGTAGACGAAGAGCATCACGAG3xe2x80x2 as anti-sense primer; an Accli-Styl fragment, sense primer 5xe2x80x2CTCGTGATGCTCTTCGTCTCACGCGC3xe2x80x2 and anti-sense primer 5xe2x80x2GTGAAGGTGCCCATGATGAGACCCAAGG3xe2x80x2 and a Styl-TAG fragment, with sense primer 5xe2x80x2CCCTGTGCACCTTGGGTCTCATCATGG3xe2x80x2 and anti-sense primer 5xe2x80x2CCTCTGCCCCGGTTACCTACCC3xe2x80x2. The corresponding primer sequences are described in Mantzoros, C. S., et.al., Diabetes 45: 909-914 (1996). The four fragments are ligated into a pUC 18 plasmid (Gibco-BRL) and sequenced. Full length xcex23 AR clones (402 amino acids) containing the last 6 amino acids of hxcex23xe2x80x94AR are prepared with the xcex23-PARpcDNA3 from ATTC.
Binding Procedure: Clones expressing receptor levels of 70 to 110 fmoles/mg protein were used in the test procedures. CHO cells were grown in 24-well tissue culture plates in Dulbecco""s Modified Eagle Media with 10% fetal bovine serum, MEM non-essential amino acids, Penicillin-Streptompycin and Geneticin. On the day of test procedure, growth medium was replaced with preincubation media (Dulbecco""s Modified Eagle Media and incubated for 30 minutes at 37xc2x0 C. Preincubation medium was replaced with 0.2 ml treatment medium containing DMEM media containing 250 xcexcM IBMX (isobutyl-1-methylxantine) plus 1 mM ascorbic acid with test compound dissolved in DMSO. Test compounds were tested over a concentration range of 10xe2x88x929 M to 10xe2x88x925 M for xcex23 cells and 10xe2x88x928 to 10xe2x88x924 M for xcex21 and xcex22 transfected cells. Isoproterenol (10xe2x88x925 M) was used as an internal standard for comparison of activity. Cells were incubated at 37xc2x0 C. on a rocker for 30 min with the xcex23 cells and 15 min for xcex21 and xcex22 cells. Incubation was stopped with the addition of 0.2N HCl and neutralized with 2.5N NaOH. The plates, containing the cells and neutralized media, were stored at xe2x88x9220 degrees celsius until ready to test for cAMP using the SPA test kit (Amersham).
Data Analysis and Results: Data collected from the SPA test procedure were analyzed as per cent of the maximal isoproterenol response at 10xe2x88x925 M. Activity curves were plotted using the SAS statistical and graphics software. EC50 values were generated for each compound and the maximal response (IA) developed for each compound is compared to the maximal response of isoproternol at 10xe2x88x925 M from the following formula:   IA  =            %      ⁢              xe2x80x83            ⁢      activity      ⁢              xe2x80x83            ⁢      compound              %      ⁢              xe2x80x83            ⁢      activity      ⁢              xe2x80x83            ⁢      isoproterenol      
Table I shows the xcex23-adronergic receptor EC50 and IA values for the representative compounds of this invention that were evaluated in this standard pharmacological test procedure. These results show that compounds of the present invention have activity at the xcex23-adrenergic receptor. The compounds of this invention had weaker or no activity at xcex21 and/or xcex22-adrenergic receptor.
Based on the results obtained in these standard pharmacological test procedures, representative compounds of this invention have been shown to be selective xcex23 adrenergic receptor agonists and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
As used in accordance with this invention, the term providing an effective amount means either directly administering such a compound of this invention, or administering a prodrug, derivative, or analog which will form an effective amount of the compound of this invention within the body.
It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. As used in accordance with invention, satisfactory results may be obtained when the compounds of this invention are administered to the individual in need at a daily dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form. For most large mammals, the total daily dosage is from about 3.5 mg to about 140 mg. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, , xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 1 to 1000 ppm of the compound in the feed. Animal feed supplements can be prepared by admixing about 75% to 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like. The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed. The supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed. The preferred poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
For parenteral administration the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought. In general, parenteral administration involves injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.001 to 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.001 to 35 mg/kg/day of body weight.
Paste formulations can be prepared by dispersing the active compounds in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like. Pellets containing an effective amount of the compounds of the present invention can be prepared by admixing the compounds of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process. It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal""s body. For the poultry and swine raisers, using the method of the present invention yields leaner animals.
Additionally, the compounds of this invention are useful in increasing the lean mass to fat ratio in domestic pets, for the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished.